PROJECT SUMMARY We have identified the statin drugs (`statins') as a potential adjunctive therapy for patients with severe asthma. Statins exert potent anti-inflammatory and immune modulatory effects in many different animal disease models including asthma. Mevalonate (MA) is the immediate product of HMG-CoA reductase (HMGCR) which is metabolized to essential metabolites for cell signaling and diverse cellular functions. All statins inhibit HMGCR, the rate-limiting step in cholesterol biosynthesis. Using our asthma mouse model, we showed that blockade of MA production with a statin abrogates allergen-induced eosinophilia, goblet cell metaplasia, and airway hyperreactivity. Multiple retrospective clinical studies have shown a positive correlation between statin use and improved asthma outcomes, including steroid-sparing effects. However, several small randomized clinical trials (RCTs) using statins have yielded conflicting results. Differences in study design, statin class (lipophilic vs. hydrophilic), lack of asthma phenotyping, and short treatment durations may account for these inconclusive findings. The choice of statin based on drug lipophilicity is an underappreciated variable in designing asthma trials, and may be a key determinant regarding which statin achieves the highest concentrations in the airway compartment. If statins are to have a clinical benefit in asthma, they must first reach the airways in high enough concentrations (i.e. ?airway distribution?) to be therapeutic. Given that statins' extrahepatic peripheral tissue distribution can vary according to drug lipophilicity, the most lipophilic statins like simvastatin are predicted to achieve higher peripheral tissue levels than the hydrophilic statins such as rosuvastatin. However, we do not know if this phenomenon occurs in the human lung and airways since it has never been measured. Our preliminary data show that the greater the statin lipophilicity, (i) the greater the airway epithelial drug concentration in severe asthmatics, and (ii) the greater its anti-inflammatory potency in vivo. Therefore, our central hypothesis is that lipophilic statins will achieve significantly higher airway epithelial concentrations and greater therapeutic efficacy than the hydrophilic statins. We will test this hypothesis with two Aims: Aim 1: To determine which class of statins has the greatest airway distribution in a prospective pilot study of human subjects undergoing elective bronchoscopy. Aim 2: To determine which class of statins has the greatest efficacy in a mouse model of chronic allergen-induced asthma. Accomplishing this work will allow us to select the right statin(s), and therefore, directly inform the rational design of forthcoming statin clinical trials for the treatment of severe asthma. This knowledge may also extend to other lung or airway diseases that could potentially benefit from treatment with statins.